Citation of documents: Please do not cite the URL that is displayed in your browser location input, instead use the DOI, URN or the persistent URL below, as we can guarantee their long-time accessibility.

Abstract

Cx36 is an important gap junction forming protein that couples GABAergic interneurons in the brain and insulin secreting beta-cells in the pancreatic islets of Langerhans. To investigate the function of this protein, knock-out mice have been generated and the phenotype of Cx36-/- males has been characterized at the anatomical, in vitro and in vivo electrophysiological as well as at the behavioral level. These studies showed that ablation of Cx36 leads to uncoupling of fast-spiking interneurons and impaired gamma-oscillations of the hippocampus. Also, the in vitro insulin release kinetics of pancreatic beta-cells are altered by loss of Cx36. To further elucidate the functional role of cell coupling mediated by Cx36 we extended the study to female Cx36-/- mice and compared their phenotype with the phenotype of male Cx36-/- mice. We found that, in contrast to males, Cx36-/- females were hyper-active in a novel environment. The activation of the dentate gyrus was impaired as indicated by cFos expression studies. Analysis of anatomical markers in conjunction with BrdU birthdating studies provided evidence that in Cx36-/- females the population of immature calretinin expressing granule cells was expanded and that their maturation was delayed. To investigate possible mechanisms linking the lack of Cx36 to alterations in adult neurogenesis and explaining the gender specificity of the neurological phenotype, it was crucial to analyze the effect of Cx36 ablation outside of the brain. These analyses showed that in female Cx36-/- mice serum insulin was increased and that dysfunctional ovaries led to decreased serum estradiol. Correlative evidence suggests that the decrease in estradiol, caused by ovarian dysfunctionality, is a direct consequence of enhanced insulin action on GnRH neurons in the hypothalamus. Additionally, we propose that chronically decreased estradiol is the reason for the delay in hippocampal granule cell maturation, which likely causes the observed alterations in the activation pattern of the dentate gyrus. Taken together, global ablation of Cx36 leads to a complex phenotype encompassing reproduction, metabolism and cognition. Currently, neuron-specific Cx36 knock-out mice are being generated that will help test the link between the hormonal alterations and neurological and behavioral phenotype.